Helicobacter pylori (H. pylori), one of the main predisposing factors for the development of gastric cancer (GC), is a key factor affecting intracellular ROS and iron metabolism. Ferroptosis is characterized by iron-dependent regulated cell death resulting from excessive lipid peroxidation and is a significant process in this context. Nevertheless, the intricate relationship between H. pylori and ferroptosis remains elusive. In this study, we find a suppressive effect of H. pylori on ferroptosis. Specifically, H. pylori inhibits RSL3/Erastin-induced ferroptosis in GC cells via Vacuolating cytotoxin A (VacA). Mechanistically, VacA binds to p62 and KEAP1, disrupting their interaction and preventing KEAP1 degradation. This stabilization of KEAP1 inhibits NRF2 nuclear translocation and subsequently suppresses HMOX1 transcription, leading to reduced Fe2+ accumulation and inhibition of ferroptosis. Additionally, cisplatin induces ferroptosis in GC cells, and HMOX1 overexpression further enhances its cytotoxic effect. Finally, we identify that Hemin (an HMOX1 inducer) enhances the antitumor effect of cisplatin in both a cell line-derived xenograft gastric cancer model and a H. pylori-induced murine gastric cancer model. These findings unveil a previously unrecognized role of H. pylori in conferring resistance to ferroptosis and identify HMOX1 as a potential therapeutic target for H. pylori-associated GC. Mechanistic dissection of H. pylori VacA– mediated suppression of ferroptosis reveals a KEAP1/NRF2/HMOX1 axis that modulates cisplatin sensitivity in gastric cancer.
原文链接
分享
引用
